Regulation, Memory and Inflammation in Transplantation

尽管在一些啮齿动物模型中诱导移植耐受“相对”容易，但同样的方法也是如此。 通常很难转化为更大的动物和患者。原因之一是小动物 模型常常不能解释记忆的障碍。除了这个已知的障碍，越来越多的证据表明， 表明炎症（其可能由于排斥、缺血-再灌注损伤、感染 等等）。也能抑制耐受诱导。 这个项目的中心原则是，在移植过程中，两个事件发生得非常早， 炎症和抗原接触，可以通过调节免疫反应来决定移植物的结果和耐受易感性。 调节细胞和效应/记忆细胞之间的平衡。我们的理论框架是， 植入引发了调节和效应器/记忆发育之间的“竞赛”或“竞争”，并且 这对移植的结果至关重要。我们的目标是检验以下假设： 促进供体特异性记忆的发展，同时抑制 调节（目标#1）;除了已知对效应子/记忆发育的影响外， 也塑造了Treg的发展（目标#2），而在这种情况下， 然而，如果使用连续的方法，则可以利用记忆来阻止记忆反应（aim #3）。这项工作对于项目#1的研究非常重要，特别是那些专注于如何 TIM 1：TIM 4通路影响Treg的产生和转化。。此外，亦会与 项目#3，特别是在细胞因子和炎症如何相互作用影响记忆和 调节，以及共刺激阻断如何影响这些过程。 我们带来了一些对这些研究至关重要的重要工具。通过我们正在进行的 与Terry Strom和Mo Sayegh的相互作用作为PPG的一部分，我们已经获得了foxp 3-GFP敲入 小鼠这些珍贵的动物可用于单独研究的稳定性，扩大和功能， 天然产生的TcR，以及抗原/精氨酸诱导的TcR的转化、扩增和功能。在 除了这些动物，其他资源包括MHC II类同种异体反应性TCR转基因小鼠，MyD 88- 缺陷小鼠，以及所有这些品系之间的杂交。 总的来说，这些研究将提供重要的新见解的分化和命运， 同种异体反应性T细胞在体内，定义这些事件是如何通过炎症和抗原相遇调节的， 并探索通过调节性T细胞控制记忆性T细胞反应的方法。

Despite the "relative" ease of inducing transplant tolerance in some rodent models, the same approaches have often proven difficult to translate into larger animals and patients. One reason is that small animal models often fail to account for the barrier of memory. In addition to this known hurdle, increasing evidence indicates that inflammation (which may occur as a result of rejection, ischemia-reperfusion injury, infection etc.) can also inhibit tolerance induction. The central tenet of this project is that two events occurring very early during the process of engraftment, inflammation and antigen encounter, can determine graft outcome and tolerance susceptibility by modulating the balance between regulatory cells and effector/memory cells. Our theoretical framework is that engraftment initiates a "race" or "competition" between regulation and effector/memory development, and the result of this is crucial to the outcome of the graft. Our aims will test the hypotheses that: inflammation promotes the development of donor specific memory, while at the same time inhibiting the development of regulation (aim #1); that antigen encounter, in addition to its known effects on effector/memory development also shapes Treg development (aim #2), and that regulation which is "dysfunctional" in the context of memory, can nonetheless be harnessed to block memory responses if adjunctive approaches are use (aim #3). This work will be important for the studies in project #1, in particular those that focus on how the TIM1:TIM4 pathway effects Treg generation and conversion. .There will also be close interactions with project #3, particularly in the area of how cytokines and inflammation interact to affect memory and regulation, and how costimulatory blockade affects these processes. We bring a number of important tools that will be critical to.these studies. Through our ongoing interactions with Terry Strom and Mo Sayegh as part of the PPG, we have obtained foxp3-GFP knock-in mice. These valuable animals can be used to separately study the stability, expansion and function of naturally arising Tregs, and the conversion, expansion and function of antigen/cytokine-induced Tregs. In addition to these animals, other resources include MHC class II alloreactive TCR transgenic mice, MyD88- deficient mice, and crosses amongst all of these strains. Collectively, these studies will provide important new insights into the differentiation and fate of alloreactive T cells in vivo, define how these events are modulated by inflammation and antigen encounter, and explore approaches that will allow for the control of memory T cell responses by regulatory T cells.